This invention relates generally to a pharmaceutical product having immunomodulating properties. More particularly, the invention relates to a biologic response modifier (BRM), defined as an agent that modifies the relationship between a disease and host by modifying the host's biological response to the disease with resultant therapeutic effects. The BRMs can be divided into two categories: (1) biologic or chemical agents that can stimulate or otherwise alter one or more of the host's resistance mechanisms and (2) purified cellular products that demonstrate direct effects on a particular disease. The first group of BRMs, in which the present invention falls, consists of agents that activate, increase, or otherwise modify host immunologic reactivity and are generally referred to as immunomodulators.
A BRM may be used alone, or in combination with other agents, to enhance resistance to or recovery from invasion by pathogens, to modify or induce tolerance to grafts of foreign tissue, to enhance tumor rejection or stabilization and to inhibit tumor recurrences following other forms of therapy, to restore normal helper-suppressor mechanisms, or otherwise promote a normal immune response.
A wide variety of immunomodulators/ immunoadjuvants has been developed since the early 1900s. The vast majority of these agents are of microbial (bacterial/fungal) origin with the most popular ones being derived from the Corynebacteria, Mycobacteria and Nocardia genera (CMN organisms). The various immunoadjuvants are comprised of either intact viable cells, dead cells, cell walls, various cell wall fractions, endotoxin, various types of polysaccharides, or subcellular fractions such as ribonucleic acid or ribosomes. Although all of these agents have demonstrated immune potentiating/modulating/adjuvant activity in tissue culture, animals, and humans, against infectious and neoplastic disease, they are universally plagued with inconsistencies in production and composition, and have moderate to severe toxicity. Relative to the treatment of neoplasia, only a few of these agents have thus far been useful in the treatment of established disease. Moreover, these agents typically demonstrate loss of activity with repeated use (anergy), hypersensitivity reactions, development of chronic inflammatory conditions, and/or the development of various other undesirable conditions.
Because of the inability to chemically define these agents due to their impurity and/or complexity, and in an attempt to reduce the variability of the immune responses and toxic complications, a number of investigators either have extracted various specific fractions from these sources or have synthesized various components demonstrating immunologic activity. Examples of specific fractions that have been investigated include the cell wall fraction muramyl tripeptide, staphlococcal protein A, various polysaccharides, the RNA fraction.sup.1/, and the ribosomal fraction.sup.2-5/.
With respect to the ribosomal fraction, the mechanism of action differs according to the ribosome source. Although the majority of ribosomal vaccines require adjuvant for activity, ribosomal vaccines prepared from Staphylococcus aureus and Neisseria meningitis do not..sup.2/ In addition, ribosomal vaccines prepared from Mycobacterium tuberculosis.sup.3/ and Salmonella typhimurium.sup.4/ appear to induce a cell-mediated response, whereas those prepared from Streptococcus pneumoniae and Streptococcus pyogenes mediate a humoral response. .sup.5/ Even though the extracted ribosomal fraction is, theoretically, the active agent, considerable controversy exists in many cases as to whether other cell components (RNA, protein, endotoxin, cell wall) present as contaminants are responsible for the observed immune reactivity.
Known cell fraction vaccines may sometimes be appropriate for the prophylactic or therapeutic treatment of infectious disease. However, they are, for several reasons, inappropriate for use as nonsensitizing general immunomodulators for the treatment of neoplastic disease. The presence of cell wall, endotoxin, or poorly degradable components often results in toxicities similar to those obtained with the intact organisms. Moreover, undesired immune suppressive and complex immune responses may be elicited since such vaccines are typically derived from organisms which are part of or which readily cross-react (common antigens) with the host's own microflora. Such vaccines also typically contain fractions having physical and/or chemical characteristics which may be suboptimal for general immune potentiating activity.
Urban, et al..sup.6/ reported on the ability of polyribosomes (aggregates of ribosomes) obtained from a specific bacterial organism to suppress the development of cutaneous SaD2 fibrosarcomas in DBA/2 mice. Polyribosome fractions were obtained from cell cultures by lysing the cells osmotically or mechanically (depending on the type of bacteria), followed by differential centrifugation. Although the effect on the SaD2 murine tumor was positive, the mechanism of the induced biological response could not be determined from the data. Although toxicity was significantly low, the process described by Urban, et al. resulted in an extreme variation in polysome profile (size distribution) and a very low product yield. Consistency of quality, stability and effectiveness was not established.
Kirsh, et al..sup.7/ have reported on immune stimulation and modulation via encapsulation of specific antigens or biologic response modifiers in liposomes. Liposomes containing drugs have been utilized for the treatment of metastatic cancer..sup.8/ However, the treatment of neoplastic disease (cancer) with biologic response modifiers alone or encapsulated in liposomes far been discouraging. Although encapsulated BRMs surpass non-encapsulated BRMs in efficacy, the limitation of therapeutic benefit may be due to immune activation being limited to the macrophage. The numbers of macrophages in these cases have been too low to effectively mediate, by themselves, the destruction of large tumor burdens.
It is an object of the present invention to provide an improved biologic response modifier.
It is another object of the invention to provide an improved biologic response modifier which exhibits minimal toxicity and immune suppression.
Another object of the invention is to provide an improved biologic response modifier which is capable of manufacture with consistent quality, stability and effectiveness.
Still another object of the invention is to provide a method for making the foregoing biologic response modifier which provides consistent quality and high yield.